Motor neurone disease genetic marker discovery

A genetic variant linked to the most common form of motor neurone disease, which holds potential as a genetic marker to better treat the neurological disease, has been discovered by researchers at the Perron Institute and Murdoch University.

The study represents a step forward in the quest to find new genetic markers to understand and advance new approaches to treat the complexities of motor neurone disease (MND).

MND is a neurodegenerative disease resulting in progressive paralysis. An estimated five to ten percent of cases are familial (hereditary), but most are sporadic.

Study marks first genetic association of its kind in MND research to be published

The collaborative research investigated the Stathmin-2 gene, which is necessary for neuron growth and regeneration. The team uncovered a structural variant within this gene that is linked to sporadic amyotrophic lateral sclerosis (ALS), the most common form of MND.

Results indicate that the variation is a risk factor and may affect the progression of the disease in some patients.

Professor Anthony Akkari, senior author of the study who heads the Motor Neurone Disease Genetics and Therapeutics Research team at the Perron Institute and Centre for Molecular Medicine and Innovative Therapeutics at Murdoch University explained.

“Identifying variations in genetic makeup is a key element in improving approaches to preventing, diagnosing and treating diseases such as MND.

“Overall, in this area of unmet need, the aim is to discover what therapies would work best for specific patient groups. Our research is aimed at filling in genetic pieces of the puzzle.

“As well as giving us a better understanding of disease mechanism, knowledge of this variant could improve outcomes of clinical trials. Grouping participants by this genetic marker would enable researchers to investigate whether the sub-group responds differently to a particular therapy.”

Frankie Theunissen and Prof Anthony Akkari at Perron Institute
Lead researchers Frankie Theunissen and Prof Anthony Akkari at the Perron Institute

Frances Theunissen was lead investigator of the study, a research assistant and PhD candidate at the Perron Institute and Murdoch University.

“This newly discovered genetic variant has the potential to be a disease marker and tool for cohort enrichment in future MND clinical trials and this strategy should become standard practice,” she said.

“It’s a step towards developing new, personalised treatments for motor neurone disease.”

Frances Theunissen

The study was published in the journal Frontiers in Aging Neuroscience.

The collaborative study involved renowned local researchers and international collaborators, including Professors Don Cleveland, John Ravits and Dr Ze’ev Melamed (University of California, San Diego), Professor Richard Bedlack (Duke University, North Carolina) and Professor Alan Mackay Sim (Griffith University, Queensland).

The research was made possible thanks to funding from the Perron Institute, the Giumelli Foundation, Ian Potter Foundation, Racing for MNDi Foundation and the Pierce Armstrong Foundation.

Changing the way we treat skin cancer

Researchers at the Illawarra Health and Medical Research Institute are leading a multi-institutional research project to better understand and treat squamous cell carcinoma (SCC) of the skin, one of the most common skin cancers in Australia.

Thanks to three-year funding from the National Health and Medical Research Council, IHMRI’s Senior Professor Marie Ranson and Associate Professor Bruce Ashford, who are leading the project, are investigating molecular changes of the cancer to determine what causes it to spread.

“SCC of the skin is so common amongst Australians, but we still don’t know why some tumours spread to nearby lymph nodes and why others do not,” Senior Professor Ranson said.

“Our aim is to decipher the molecular changes that distinguish those SCCs that are likely to spread so that clinicians can identify and treat these patients early.”

Senior Professor Marie Ranson

A better prognosis, more targeted treatments

The project aims to achieve better prognosis and more targeted treatments for one of Australia’s most common cancers and major healthcare burdens.

Patients with aggressive variants of cutaneous SCC often present late, when the cancer has already spread through lymphatics to nodes in the neck.

“When patients present at such a late stage, we have to treat with both radical surgery and high dose radiotherapy. Even then, the chances of surviving beyond five years are only about 50%,” A/Professor Ashford explained.

“We want to be able to identify whether there are early markers that distinguish whether we can avoid unnecessary surgery, or whether we should use even more aggressive treatment.”

Associate Professor Bruce Ashford

Understanding the genetic landscape

Senior Professor Ranson, A/Professor Ashford and the IHMRI team are unravelling the genetic landscape of SCC through the process of whole genome sequencing. Through this process, researchers can see if there is a signature within these tumours that can help predict which ones will spread.

“If we find a signature, it will enable clinicians to more accurately identify at-risk patients to diagnose and treat metastatic SCC early. We have so far completed whole genome sequencing on 33 patient specimens and are completing RNA sequencing of these tumours,” Senior Professor Ranson explained.

The tumour samples are collected from surgery at both Wollongong Hospital and the Chris O’Brien Lifehouse in Sydney. Whole genome sequencing works by comparing cancer cells to normal cells to check for mutations in the DNA. If researchers can find a common pattern of mutation within the cancers, it will help identify which tumours will spread.

“Over three years we hope to examine between 60 and 80 patient specimens. This grant also helps fund the employment of bioinformaticians to help us understand the complex nature of DNA variation in this deadly disease,” said Senior Professor Ranson.

The project is a collaboration with partners, Associate Professor Ruta Gupta from Royal Prince Alfred Hospital, and Professor Narayanan Gopalakrishna Iyer from the National Cancer Centre in Singapore.

A Hudson Institute researcher has identified problems and potential solutions with new gene targeting medicines that could change the way these are made to help patients.

Headshot of Associate Professor Michael Gantier
Associate Professor Michael Gantier

Gene targeting medicines—nucleic acid therapeutics—are an emerging category of medicine with huge potential to improve the lives of patients. Based on synthetic nucleic acids (DNA and RNA), nucleic acid therapeutics target diseases at the genetic level, by preventing the expression of disease-causing proteins. This new category of medicines could benefit patients by replacing daily medication with injections administered only several times a year.

A study led by Hudson Institute researcher A/Prof Michael Gantier published in Nucleic Acids Research has established that common modifications used to stabilise these nucleic acid treatments are immunosuppressive, meaning that these treatments could selectively block some key sensors of our immune system which normally alert us to infections.

Led by A/Prof Gantier and including PhD student Arwaf Alharbi and Masters student Aurelie Garcin, the study investigated how synthetic nucleic acid molecules interact with the body’s immune system.

“The immune-stimulatory effect of some nucleic acid therapeutics has been known for more than 15 years. However, how these molecules can block the immune response has been understudied,” said A/Prof Gantier.

“We discovered that one class of nucleic acids-based therapeutics was prone to unintended immune suppression, specifically, inhibiting a sensor called Toll like receptor 7 (TLR7),” Dr Gantier said.

“While these molecules are used to target a specific disease, they can also shut down some of the key sensors in the body’s immune response. This could cause strong side effects in patients infected by pathogens after injection with these molecules.”

“If a patient gets the flu or a bacterial infection a few days after getting an injection with nucleic acid therapeutics, this may put them at increased risk of infection. It will only be a problem when a patient gets an infection, so this is a new issue that has not been on researchers’ radar. However, as these technologies become more broadly used, there is an increased potential for patient complications,” A/Prof Gantier said.

Solutions identified

In addition to identifying the problem, the study has also found molecular designs that could be used to avoid these immunosuppressive effects, keeping the immune response in check to defend against infection.

“While we discovered a frequent problem with these molecules we have also provided molecular designs to solve it. This could change the way this new class of therapeutics is made, and help many patients.”

“Many new drugs currently in development based on nucleic acids could be affected,” he said.


More information

What are nucleic acids?
DNA and RNA are a category of molecules known as nucleic acids, which contain and access the genetic information controlling which cells do what in our bodies. Nucleic acids are present in every life form, including bacteria and viruses, and are essential for our immune system to detect infections.

How are these medicines being used?
Several nucleic acid medicines have recently been approved for use in humans, for instance treating some cases of muscular dystrophies. Others are in clinical trials targeting a range of conditions including neurological diseases, cancer, and hypercholesterolemia – which affects about one in 200 people. The therapeutics are also being used to develop anti-viral drugs.

Australian first gene therapy for childhood blindness

Two Sydney siblings have become the first patients in the country to receive a novel gene therapy that has rescued their vision and holds hope for preventing them from going blind.

The ocular gene therapy, LUXTURNA, is the world’s first approved gene replacement therapy for an inherited blinding eye condition and one of the first gene replacements for any human disease. Approved by the Therapeutic Goods Administration, LUXTURNA is used to treat children and adults with biallelic pathological mutations in RPE65, a rare mutation that leads to vision loss and blindness. It is being distributed in Australia by Novartis.

Therapy has stopped progressive vision loss

Seventeen-year-old Rylee and 15-year-old Saman were both diagnosed with Leber congenital amaurosis, a severe form of retinal dystrophy, in their first year of life. They received the life-changing therapy at The Children’s Hospital at Westmead in late 2020 and early 2021. The therapy has stopped their progressive vision loss and led to some improvements in their vision.

The therapy was delivered as part of Ocular Gene and Cell Therapies Australia (OGCTA), a new collaboration involving the Genetic Eye Clinic at Sydney Children’s Hospitals Network (SCHN), the Eye Genetics Research Unit and Stem Cell Medicine Group at the Children’s Medical Research Institute (CMRI), and the Save Sight Institute at Sydney Eye Hospital and University of Sydney.

CMRI’s Gene Therapy Research Unit

Revolutionary therapy

CMRI was represented on this project by Professor Frank Martin who is CMRI’s Board President, Professor Robyn Jamieson, Head of the Eye Genetics Research Unit at CMRI and SCHN and Dr Anai Gonzalez Cordero, Head of the Stem Cell Medicine Group and Professor Ian Alexander, Head of the Gene Therapy Research Unit and their teams.

Professor Jamieson is also lead of OGCTA and Head, Specialty of Genomic Medicine, University of Sydney. She said the therapy was revolutionary and would lead to transformation of care for patients with blinding eye diseases.

Professor Robyn Jamieson

“Inherited retinal disease is a devastating diagnosis. Up until now, these patients suffered progressive vision loss that led to blindness and there was no therapy for them at all.”

Professor Jamieson

“But through new genomic diagnostics and the use of ocular gene therapy, we are finding that we have the ability to not only stop this ongoing progression but also help to improve vision for people who have RPE65-related retinal vision loss.”

Children and adults born with a mutation in both copies of the RPE65 gene can suffer from a range of symptoms, including night blindness (nyctalopia), loss of light sensitivity, loss of peripheral vision, loss of sharpness or clarity of vision and potentially total blindness.

Replacing faulty genes

Ocular gene therapy works by injecting LUXTURNA under the retina and carrying a functioning RPE65 gene to replace the faulty one, thereby preventing some of these devastating symptoms.

luxturna Team – the team who delivered Australia’s first gene therapy for a blinding eye condition

“The real-world improvements in visual function has been quite remarkable bringing to life the rather dry clinical trials outcome measures,” said Professor John Grigg, Head of Specialty of Ophthalmology, Save Sight Institute, University of Sydney and lead inherited retinal disease specialist in OGTCA said.

“It is tremendously heartening to see the changes in vision capabilities for these first patients treated with LUXTURNA.”

Professor Grigg

“As an ophthalmologist who has been caring for patients with Leber’s amaurosis for many years and unable to offer any treatment, it is incredibly rewarding to now have the opportunity to not only give families hope but also be involved in improving their child’s vision,” said Frank Martin, Clinical Professor in the Specialties of Paediatrics and Child Health and Ophthalmology at the University of Sydney said.

Associate Professor Matthew Simunovic, Vitreoretinal Surgeon, Sydney Eye Hospital and SCHN and Associate Professor at the Save Sight Institute, University of Sydney performed the first surgery and said the benefits of treatment should extend well into the future.

“This is incredibly delicate surgery in which LUXTURNA is injected under the retina, which in some patients can be as thin as a sheet of copy paper. Riley and Saman have had profound improvements in their vision, which mirror the results seen in the pivotal clinical trials.”

“Importantly, such benefits appear to be sustained for many years – in fact, for as long as patients have been followed up. Successfully delivering the first approved gene therapy has been a fantastic team effort, and it underscores Australia’s capability in this field.”

A/Prof. Simunovic

To date, this treatment has been used to treat four patients and while it can only be used to treat this specific form of retinal disease, it does provide significant hope that similar treatments will be able to be applied to other retinal disease genes in the future.

“This heralds a new era in transforming the lives of these people who otherwise have a life of blindness ahead of them and provides hope for more than 15,000 other affected Australians who live with some form of inherited retinal disease,” Professor Grigg said.

Read more about this story on ABC News.

Hunt for facial deformity gene ends after 20-year search

A new disease gene discovery began with a Perth PhD student and the world’s largest known family with the disease. Twenty years later Yale University U.S.A. re-found that research, compared it to affected American families, asked the Perth team to re-look at the original DNA and found a match.

Hunting for disease genes is like putting together an international jigsaw puzzle. The DNA of families across the globe often contributes to the necessary process of cross-referencing discoveries of tiny segments of genetic code to see if they match.

One of the world’s best, Professor Nigel Laing AO at Perth’s Harry Perkins Institute of Medical Research says it’s a Eureka moment whenever a discovery is made.

“In that moment you know you are looking at something no-one else has ever seen, the precise genetic mutation causing a disease that’s affecting families around the world and when you make that discovery you know those families will finally get the answer that they have longed for,” he said.

Families with hemifacial microsomia, a condition where one side of the face is underdeveloped and does not grow normally, have just joined that rarefied group.

Their disease gene has been found.

For the first time families affected by the condition will be able to find out if they are passing it on to the next generation.

Hemifacial microsomia is the second most common facial congenital disability after cleft palate. It affects one in every 3,500 to 4,000 births.

In a very small number of cases, hemifacial microsomia is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. For an adult with the affected gene, each of their children has a 50 percent chance of inheriting the condition.

The disease develops in utero and babies born with facial deformities can need breathing support or a tracheostomy soon after birth if the jaw is severely affected. The condition does not improve with growth, in fact deformities can get worse.

Children with hemifacial microsomia have an increased risk of hearing loss, speech impairment, and feeding problems and, unsurprisingly, can experience psycho-social challenges in childhood.

The hunt begins

Twenty years ago, a hunt for the disease gene began in Perth, Western Australia.

PhD student, now Dr David Chandler, started working with the biggest known family with the condition.

Nine members of the same family were affected. They had been seen by Genetic Services WA, the Department of Health’s clinical genetics service, which works with families to diagnose their condition if possible and provide genetic counselling if wanted.

David Chandler commenced the arduous process of analysing the family’s DNA for clues about what might be causing this genetic disease to see if a diagnosis could be made.

His PhD was supported by a UWA PhD Scholarship and by the National Health and Medical Research Council (NHMRC) Project Grant associated with the NHMRC Fellowship that Professor Laing held at the time.

Internationally renowned geneticist Professor Nigel Laing AO, Head of the Genetic Disease Group at the Harry Perkins Institute of Medical Research, jointly supervised the PhD.

At the time the technology available, limited the search.

“We could narrow down the hunt from three billion base pairs of DNA to 14 million.”

Professor Nigel Laing AO

“We were looking for DNA markers shared by everyone who had the disease and David Chandler found that on a region on a particular chromosome, but without the genetic sequencing technology available today, it wasn’t possible to refine the search further.”

“We also needed to cross reference our findings with other families with the condition. We knew of research in Germany but it looked like that family’s condition was on a different chromosome,” he said.

Despite not being able to take the research further the proposed chromosome region of the gene was published in 2001.

Two decades later

Dr David Chandler was awarded his PhD and now works at the Australian Genome Research Facility at Royal Perth Hospital.

Professor Laing is Head of the Preventive Genetics Group at the Harry Perkins Institute of Medical Research where his lab has been involved in the discovery of more than 30 disease genes including one that bears his name, Laing distal myopathy, a condition that causes progressive muscle weakness from childhood.

Professor Laing’s team variously receives support from the NHMRC through Fellowship, Project and Ideas Grants and the Medical Research Future Fund.

In recent years the team has also been generously supported by The Fred Liuzzi Foundation in Melbourne, The Zac Pearson Legacy in Perth and the family of the late Dr Patricia Kailis AM, OBE, FTSE who conducted world leading genetic research before the mapping of the human genome had occurred. Dr Kailis recorded the world’s first decrease in the incidence of an inherited disease as a result of genetic counselling.

Her family has established the Patricia Kailis Fellowship in her honour to provide funding for mid-career researchers focused on unlocking the secrets and providing treatments for rare genetic diseases.

The link with America

Last year the senior authors on the West Australian 2001 paper were contacted by Professor Andrew Timberlake at Yale University in the U.S.A.

His laboratory had been analysing the genetic code of six other families with hemifacial microsomia, mostly from the USA.

“He said he had identified a possible gene for hemifacial microsomia in the region on the chromosome that matched the region identified 20 years before in our research,” said Professor Laing.

“Professor Timberlake found variants which knocked out the function of a particular gene affecting the growth patterning that influences facial development.

“He’d scoured the published literature and found our 20-year-old research and contacted us.

The Yale University group were very keen to know whether the Perth family’s DNA had been kept and could be again accessed. They were still believed to be the largest affected family in the world.

The answer was yes.

“We still had DNA of members of the Perth family and Genetic Services WA recontacted the family and updated the family tree which now had 12 affected family members.

“Collaborating with Diagnostic Genomics in Pathwest we discovered that the Perth family also had the function of the gene knocked out.

“Finally, we could say that the gene causing hemifacial microsomia had been found.”

Professor Laing

Dr Chandler was delighted that his research as a young student had resulted in an international discovery.

“It is incredibly exciting to have a genetic search that commenced such a long time ago resolved for families around the world,” Dr Chandler said.

Professor Laing said the discovery gives couples with a history of the disease in their family reproductive choices.

The 2021 research has been published in Nature Communications

Professor Nigel Laing and Dr David Chandler discuss finding the hemifacial microsomia gene